Various deoxy derivatives of kanamycins A, B and C as well as various 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl) derivatives of the kanamycins A, B and C are already known as the semisynthetic aminoglycosidic antibiotics which are derived from the kanamycins. These known deoxy derivatives and 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl) derivatives of the kanamycins have usefully high antibacterial activities, but the antibacterial spectra of these known derivatives of the kanamycins are of different ranges. Besides, these known kanamycin derivatives are possible to become inactive against such new resistant strains of bacteria which will possibly occur in future. Accordingly, it is always requested that new, antibacterial compounds having any more excellent properties than the known antibacterial kanamycin derivatives should be created and provided for use in therapeutic treatment of bacterial infections.
We, the present inventors, had an expectation that if we would succeed in synthetizing such a new kanamycin A derivative having the 3'-hydroxyl group replaced by a fluoro atom, namely a kanamycin A derivative identifiable as 3'-fluoro-3'-deoxykanamycin A, this new compound should be active against some kanamycin-resistant strains of bacteria which are already known and also against some another resistant strains which will possibly occur in future. With such expectation, we have made our efforts to synthetize 3'-fluoro-3'-deoxykanamycin A, and as a result of our researches we have succeeded in synthetizing 3'-fluoro-3'-deoxykanamycin A first time by a synthetic process wherein 3-deoxy-3-fluoro-1,2: 5,6-di-O-isopropylidene-.alpha.-D-glucofuranose, a known compound disclosed in the "Journal of Organic Chemistry" Vol. 43, No. 6, pages 1090-1092 (1978), is used as the starting compound and is subjected to a series of reaction steps, as described in the specification of Japanese patent application No. 161615/84 (filed Aug. 2, 1984); U.S. patent application Ser. No. 758,819, now U.S. Pat. No. 4,634,688; and European patent application No. 85 401575.7. We have also devised and provided a further process for the production of 3'-fluoro-3'-deoxykanamycin A which comprises starting from kanamycin A itself (Japanese patent application No. 261776/84, filed Dec. 13, 1984).
We have made our further research in an attempt to synthetize a new compound 3'-fluoro-3'-deoxykanamycin B and we have succeeded in synthetizing 3'-fluoro-3'-deoxykanamycin B according to a synthetic process wherein a known compound, 6'-N-, 4'-O-carbonyl-4",6"-O-cyclohexylidene-1,2',3,3"-tetra-N-tosylkanamycin B which is disclosed as an N,O-protected kanamycin B derivative in Japanese patent application first publication "Kokai" No. 63993/81; U.S. Pat. No. 4,349,666; and the "Nippon Kagaku Kaishi" 1982, No. 10, pages 1706-1712 (1982) is employed as a starting compound (Japanese patent application No. 262700/84, filed Dec. 14, 1984). We have also succeeded in synthetizing new compounds, 1-N-(DL- or L-3-amino-2-hydroxy-propionyl)-3'-fluoro-3'-deoxykanamycins A and B, as well as 1-N-(L-4-amino-2-hydroxybutyryl)-3'-fluoro-3'-deoxykanamycins A and B by acylating the 1-amino group of the 3'-fluoro-3'-deoxykanamycin A or 3'-fluoro-3' -deoxykanamycin B as newly produced by us. We have further found that these new 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl) derivatives of 3'-fluoro-3'-deoxykanamycins A and B are the new compounds having remarkable antibacterial activities against various gram-positive and gram-negative bacteria, including the resistant bacteria (Japanese patent application No. 76706/85, filed Apr. 12, 1985).
We have continued our researches and as a result, we have now succeeded in synthetizing a new compound, 2',3'-dideoxy-2'-fluorokanamycin A first time by a synthetic process in which a known compound methyl 4,6-O-benzylidene-3-deoxy-.beta.-D-arabino-hexopyranoside disclosed in the "Can. J. Chem." Vol. 49, pages 796-799 (1971), and a known compound 6-O-(3'-amino-3'-deoxy-.alpha.-D-glucopyranosyl)-2-deoxystreptamine are used as the starting compounds and are reacted with each other according to a process as described and illustrated in Examples hereinafter. We have found that the new compound 2',3'-dideoxy-2'-fluorokanamycin A now synthetized exhibits an antibacterial activity against various gram-positive and gram-negative bacteria, including various kanamycin-resistant bacteria.
We have now also succeeded in synthetizing new compounds, 1-N-(DL- or L-3-amino-2-hydroxypropionyl)-2',3'-dideoxy-2'-fluorokanamycin A and 1-N-(L-4-amino-2-hydroxybutyryl)-2',3'-dideoxy-2'-fluorokanamycin A by acylating the 1-amino group of the 2',3'-dideoxy-2'-fluorokanamycin A with DL- or L-3-amino-2-hydroxypropionic acid or L-4-amino-2-hydroxybutyric acid. We have also found that these new 1-N-(.alpha.-hydroxy-.omega.-aminoalkanoyl) derivatives of 2',3'-dideoxy-2'-fluorokanamycin A have remarkable antibacterial activities against a variety of gram-positive bacteria and gram-negative bacteria, including various resistant bacteria. Based on these findings, we have accomplished this invention.